Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZY0PM2)

• DOT Name: Calcium uptake protein 2, mitochondrial (MICU2)
• Synonyms: EF-hand domain-containing family member A1
• Gene Name: MICU2
• Related Disease:
  Neurodevelopmental disorder
  Mitochondrial disease
  Young-onset Parkinson disease
• UniProt ID: MICU2_HUMAN
• PDB ID: 6AGH; 6IIH; 6K7Y; 6LB7; 6LB8; 6LE5; 6WDN; 6WDO; 6XJV; 6XJX; 6XQN; 6XQO
• Sequence:
  MAAAAGSCARVAAWGGKLRRGLAVSRQAVRSPGPLAAAVAGAALAGAGAAWHHSRVSVAA
  RDGSFTVSAQKNVEHGIIYIGKPSLRKQRFMQFSSLEHEGEYYMTPRDFLFSVMFEQMER
  KTSVKKLTKKDIEDTLSGIQTAGCGSTFFRDLGDKGLISYTEYLFLLTILTKPHSGFHVA
  FKMLDTDGNEMIEKREFFKLQKIISKQDDLMTVKTNETGYQEAIVKEPEINTTLQMRFFG
  KRGQRKLHYKEFRRFMENLQTEIQEMEFLQFSKGLSFMRKEDFAEWLLFFTNTENKDIYW
  KNVREKLSAGESISLDEFKSFCHFTTHLEDFAIAMQMFSLAHRPVRLAEFKRAVKVATGQ
  ELSNNILDTVFKIFDLDGDECLSHEEFLGVLKNRMHRGLWVPQHQSIQEYWKCVKKESIK
  GVKEVWKQAGKGLF
• Function: Key regulator of mitochondrial calcium uniporter (MCU) required to limit calcium uptake by MCU when cytoplasmic calcium is low. MICU1 and MICU2 form a disulfide-linked heterodimer that stimulate and inhibit MCU activity, depending on the concentration of calcium. MICU2 acts as a gatekeeper of MCU that senses calcium level via its EF-hand domains: prevents channel opening at resting calcium, avoiding energy dissipation and cell-death triggering.
• Reactome Pathway:
  Processing of SMDT1 (R-HSA-8949664)
  Mitochondrial calcium ion transport (R-HSA-8949215)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[1]
Mitochondrial disease	DISKAHA3	Limited	Autosomal recessive	[2]
Young-onset Parkinson disease	DIS05LFS	Limited	Genetic Variation	[3]

5 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Calcium uptake protein 2, mitochondrial (MICU2).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Calcium uptake protein 2, mitochondrial (MICU2).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Calcium uptake protein 2, mitochondrial (MICU2).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Calcium uptake protein 2, mitochondrial (MICU2).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Calcium uptake protein 2, mitochondrial (MICU2).	[8]

References

• [1] A null mutation in MICU2 causes abnormal mitochondrial calcium homeostasis and a severe neurodevelopmental disorder.Brain. 2017 Nov 1;140(11):2806-2813. doi: 10.1093/brain/awx237.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Parkin-dependent regulation of the MCU complex component MICU1.Sci Rep. 2018 Sep 21;8(1):14199. doi: 10.1038/s41598-018-32551-7.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.